The aging brain undergoes impairment of nerve cell functions including neuronal and synaptic atrophy, receptor and neurotransmitter level decrements and myelin protein dysfunction. Two critical gene regulatory factors, the vitamin D receptor (VDR) and retinoid X receptors (RXRs), may play important roles in the pathogenesis of age-related neurodegeneration. The levels of vitamin D hormone and its receptor, VDR undergo age-related declines and the gene regulatory properties of VDR require the intimate interactions with RXRs. However, brain cell populations expressing these receptors remain to be established. The overall hypothesis of this proposal is to determine whether aging- related differences significantly affect the synthesis of these receptors species in key central neurons. To study these effects on VDR/RXR expression, we will 1) conduct neutroanatomical characterization of cell populations with synthetic capacity for these receptor species in brain regions known to undergo age-related changes, 2) quantitatively determine the effects of aging upon these receptors, and 3) correlate the observed changes in levels of VDR and RXRs with incident of apoptotic profiles within the same central loci. To successfully accomplish these goals, a multifaceted investigative approach, i.e. complementary protein, mRNA and DNA analyses, will be employed. This proposal offers a unique opportunity to examine the emerging roles of VDR and RXRs in regulation of brain functions. The results will serve as basis for further research that will explore the mechanisms of steroid actions. Moreover, forthcoming data will also serve to justify studies in human subjects to determine whether significant changes documented in the aging animal model are manifested in varying degrees in aging-associated degenerating brain pathways. These studies will provide new insights into the pathogenesis of age-related neuronal cell death and may shed new light on the contribution of vitamin D in regulation of brain function.